The pancreas comprises two glandular tissues, one, is a collection of cells that form the exocrine function of the pancreas where these exocrine cells synthesize and release digestive enzymes into the intestine; the second tissue comprises the endocrine function of the pancreas which synthesize and release hormones into the circulation. Of prime importance in the endocrine function of the pancreas, are the β-cells. These cells synthesize and secrete the hormone insulin. The hormone insulin plays a vital role in maintaining normal physiological glycaemic levels. There are molecules that are effectors of the endocrine cells of the pancreas. Incretins are an example of such molecules. Incretins potentiate glucose-induced insulin secretion from the pancreas,
Incretins such as glucagon-like peptide-1 (7-36) amide (“GLP-1”; or the lizard analog Exendin-4) and gastric inhibitory polypeptide (“GIP”) have been demonstrated to be insulinotropic, i.e., their presence or stabilization can maintain acute glycaemic control by their insulin-secretive effects (42, 18). GIP and GLP-1 are responsible for over 50% of nutrient-stimulated insulin secretion. Upon release into the circulation, GIP and GLP-1 are rapidly inactivated by the circulating enzyme dipeptidyl peptidase IV (DP IV). GIP and GLP-1 make up the endocrine component of the entero-insular (gut-pancreas) axis—a concept describing the neural, endocrine and substrate signaling pathways between the small intestine and the islets of Langerhans (9). Together, the incretins are responsible for over 50% of nutrient-stimulated insulin release, In addition, the incretins share a number of non-insulin mediated effects that contribute towards effective glucose homeostasis. GIP and GLP-1 have both been shown to inhibit gastric motility and secretion (10, 11), to promote β-cell glucose competence (12), and to stimulate insulin gene transcription and biosynthesis (13, 14). In addition, GIP has been reported to play a role in the regulation of fat metabolism (15) while GLP-1 has been shown to stimulate β-cell differentiation and growth (16), as well as to restore islet-cell glucose responsiveness (17). Additionally, it has been demonstrated that GLP-1 acts as an islet growth hormone by stimulating β-cell proliferation, cell mass increase and by promoting undifferentiated pancreatic cells to become specialized cells of the islet of Langerhans. Such cells show improved secretion of insulin and glucagon (43,44).
It has been previously proposed to apply exogenous bioactive GLP-1, or its analogs, to either stimulate islet cell regeneration in vivo, or to obtain pancreatic cells from diabetes mellitus patients and to treat such cells ex vivo in tissue culture using bioactive GLP-1. This ex vivo treatment was considered to facilitate regeneration and/or differentiation of islet cells which could then synthesis and secrete insulin or glucagon (45,46).
However, such a treatment regime requires the enteral or parenteral application of bioactive GLP-1 to patients, including the possibility of surgery. It is one aspect to obviate the need for surgical treatment, enteral or parenteral applications of bioactive GLP-1.
References
    1. Kieffer T J, McIntosh C H, Pederson R A: Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136: 3585-3596, 1995    2. Mentlein R: Dipeptidyl-peptidase IV (CD26)—role in the inactivation of regulatory peptides. Regul Pept 85: 9-24, 1999    3. Pospisilik J A, Hinke S A, Pederson R A, Hoffmann T, Rosche F, Schlenzig D, Glund K, Heiser U, McIntosh C H, Demuth H: Metabolism of glucagon by dipeptidyl peptidase IV (CD26). Regul Pept 96: 133-141, 2001    4. Suzuki S, Kawai K, Ohashi S, Mukai H, Yamashita K: Comparison of the effects of various C-terminal and N-terminal fragment peptides of glucagon-like peptide-1 on insulin and glucagon release from the isolated perfused rat pancreas. Endocrinology 125: 3109-3114, 1989    5. Schmidt W, Siegel E, Ebert R, Creuzfeldt W: N-terminal tyrosine-alanine is required for the insulin releasing activity of glucose-dependent insulinotropic polypeptide (GIP). Eur J Clin Invest 16: A9, 1986    6. Pauly R P, Rosche F, Wermann M, McIntosh C H, Pederson R A, Demuth H U: Investigation of glucose-dependent insulinotropic polypeptide-(1-42) and glucagon-like peptide-1-(7-36) degradation in vitro by dipeptidyl peptidase IV using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. A novel kinetic approach. J Biol Chem 271: 23222-23229, 1996    7. Deacon C F, Nauck M A, Meier J, Hucking K, Holst J J: Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide. J Clin Endocrinol Metab 85: 3575-3581, 2000    8. Hansen L, Deacon C F, Orskov C, Holst J J: Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140: 5356-5363, 1999    9. Unger R H, Eisentraut A M: Entero-insular axis. Arch Intern Med 123: 261-266, 1969    10. Schirra J, Katschinski M, Weidmann C, Schafer T, Wank U, Arnold R, Goke B: Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 97: 92-103, 1996    11. Pederson R A, Brown J C: Inhibition of histamine-, pentagastrin-, and insulin-stimulated canine gastric secretion by pure “gastric inhibitory polypeptide”. Gastroenterology 62: 393-400, 1972    12. Huypens P, Ling Z, Pipeleers D, Schuit F: Glucagon receptors on human islet cells contribute to glucose competence of insulin release. Diabetologia 43: 1012-1009, 2000    13. Fehmann H-C, Habener J F: Insulinotropic hormone glucagon-like peptide-1 (7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells. Endocrinology 130: 159-16., 1992    14. Drucker D J, Philippe J, Mojsov S, Chick W L, Habener J F: Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci USA 84: 3434-3438, 1987    15. Pederson R: Gastric Inhibitory Polypeptide. In: Gut Peptides (J H Walsh, G J Dockray, eds.), pp. 217-259, Raven Press, Ltd, New York, 1994    16. Hui H, Wright C, Perfetti R., Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells. Diabetes 50: 785-796, 2001    17. Zawalich W S, Zawalich K C, Rasmussen H: Influence of glucagon-like peptide-1 on beta cell responsiveness. Regul Pept 44: 277-283, 1993    18. Pauly R, Demuth H-U, Rosche F, Schmidt J, White H, McIntosh C, Pederson R: Inhibition of dipeptidyl peptidase IV (DP IV) in rat results in improved glucose tolerance (Abstract). Regul Pept 64: 148, 1996    19. Pederson R A, White H A, Schlenzig D, Pauly R P, McIntosh C H, Demuth H U: Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes 47: 1253-1258, 1998    20. Balkan B, Kwasnik L, Miserendino R, Holst J J, Li X: Inhibition of dipeptidyl peptidase IV with NVP-DPP728 increases plasma GLP-1 (7-36 amide) concentrations and improves oral glucose tolerance in obese Zucker rats. Diabetologia 42: 1324-1331, 1999    21. Lynn F C, Pamir N, Ng E H, McIntosh C H, Kieffer T J, Pederson R A: Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes 50: 1004-1011, 2001    22. Demuth H U: Recent developments in inhibiting cysteine and serine proteases. J Enzyme Inhib 3: 249-78, 1990    23. Jia X, Elliott R, Kwok Y N, Pederson R A, McIntosh C H: Altered glucose dependence of glucagon-like peptide 1(7-36)-induced insulin secretion from the Zucker (fa/fa) rat pancreas. Diabetes 44: 495-500, 1995    24. Matsuda M, DeFronzo R A: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycaemic insulin clamp. Diabetes Care 22: 1462-70, 1999    25. Brownsey R W, Denton R M: Evidence that insulin activates fat-cell acetyl-CoA carboxylase by increased phosphorylation at a specific site. Biochem J 202: 77-86, 1982    26. Thomas J A, Schlender K K, Larner J: A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem 25: 486-499, 1968    27. Pederson R A, Buchan A M, Zahedi-Asl S, Chan C B, Brown J C: Effect of jejunoileal bypass in the rat on the enteroinsular axis. Regul Pept 5: 53-63, 1982    28. Finegood D T, McArthur M D, Kojwang D, Thomas M J, Topp B G, Leonard T, Buckingham R E: Beta-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes 50: 1021-1029, 2001    29. Ahren B, Holst J J, Martensson H, Balkan B: Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Eur J Pharmacol 404: 239-245, 2000    30. Wang Y, Montrose-Rafizadeh C, Adams L, Raygada M, Nadiv O, Egan J M: GIP regulates glucose transporters, hexokinases, and glucose-induced insulin secretion in RIN 1046-38 cells. Mol Cell Endocrinol 116: 81-87, 1996    31. Wang Y, Egan J M, Raygada M, Nadiv O, Roth J, Montrose-Rafizadeh C: Glucagon-like peptide-1 affects gene transcription and messenger ribonucleic acid stability of components of the insulin secretory system in RIN 1046-38 cells. Endocrinology 136: 4910-4917, 1995    32. Demuth H-U, Hoffmann T, Glund K, McIntosh C H S, Pederson R A, Fuecker K, Fischer S, Hanefeld M: Single dose treatment of diabetic patients by the inhibitor P32/98 (Abstract). Diabetes 49 (Suppl. 1): 413-P, 2000    33. Glund K, Hoffmann T, Demuth H-U, Banke-Bochita J, Rost K L, Fuder H: Single dose-escalation study to investigate the safety and tolerability of the DP IV-inhibitor P32/98 in healthy volunteers (Abstract). Exp Clin Endocrinol Diabetes 108:159, 2000    34. Yang H, Egan J M, Wang Y, Moyes C D, Roth J, Montrose M H, Montrose-Rafizadeh C: GLP-1 action in L6 myotubes is via a receptor different from the pancreatic GLP-1 receptor. Am J Physiol 275: C675-C683, 1998    35. O'Harte F P, Abdel-Wahab Y H, Conlon J M, Flatt P R: Amino terminal glycation of gastric inhibitory polypeptide enhances its insulinotropic action on clonal pancreatic B-cells. Biochim Biophys Acta 1425: 319-327, 1998    36. Mizuno A, Kuwajima M, Ishida K, Noma Y, Murakami T, Tateishi K, Sato I, Shima K: Extrapancreatic action of truncated glucagon-like peptide-I in Otsuka Long-Evans Tokushima Fatty rats, an animal model for non-insulin- dependent diabetes mellitus. Metabolism 46: 745-749, 1997    37. Alcantara A I, Morales M, Delgado E, Lopez-Delgado M I, Clemente F, Luque M A, Malaisse W J, Valverde I, Villanueva-Penacarrillo M L: Exendin-4 agonist and exendin(9-39)amide antagonist of the GLP-1(7-36)amide effects in liver and muscle. Arch Biochem Biophys 341: 1-7, 1997    38. Young A A, Gedulin B R, Bhavsar S, Bodkin N, Jodka C, Hansen B, Denaro M: Glucose-lowering and insulin-sensitizing actions of exendin-4. Studies in obese diabetic (ob/ob, db/db) Mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes 48: 1026-1034, 1999    39. Freyse E J, Becher T, El-Hag O, Knospe S, Göke B, Fischer U: Blood glucose lowering and glucagonostatic effects of glucagon-like peptide I in insulin-deprived diabetic dogs. Diabetes 46: 824-828, 1997    40. Larsen J, Jallad J, Damsbo P: One week continuous infusion of GLP-1 (7-37) improves glycaemic control in NIDDM (Abstract). Diabetes 45: 233A, 1996    41. Rachman J, Barrow B, Levy J, Turner R: Near normalisation of diurnal glucose concentrations by continuous administrations of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 40: 205-211, 1997    42. Demuth, H. U. et al., DE 196 16 486:1-6, 1996    43. Yaekura, K. et al., IN: VIP, PACAP, and Related Peptides, W. G. Forssmann and S. I. Said (eds.), New York: New York Academy of Sciences, 1998, p. 445-450    44. Buteau, J. et al., Diabetologia 42(7): 856-864, 1999    45. Zhou, J. et al., Diabetes, 48(12):2358-2366, 1999    46. Xu, G. et al., Diabetes, 48(12):2270-2276, 1999    47. Sato, A. et al., Pancreas 2002, 25 (1), 86-93    48. Filipsson, K. et al.: Neuropeptide Pituitary Adenylate Cyclase—Activating Polypeptide and Islet Function, Diabetes, 50 (9):1959-1969, 2001    49. Sedo & Malik, Dipeptidyl peptidase IV-like molecules: homologous proteins or homologous activities, Biochimica et Biophysica Acta 2001, 36506: 1-10